The invention relates to compositions and methods for the treatment of bacterial infections in animals. More particularly, the invention relates to a composition containing an antibiotic for use in the treatment of bacterial infections in animals such as cattle, sheep and swine.
All references cited herein are hereby incorporated in their entirety by reference.
Widespread infection of cattle or other animals in a feedlot, the commingling of calves or other livestock from different sources causes the calves and other animals to be exposed to pathogens for which immunity has not developed. The stresses of shipping and change in diet reduces the calves' and other animals' immune defenses. Additionally, the poor weather of autumn, when calves or other livestock are usually moved from pastures to feedlots, further increases the risk of illness. Together, these circumstances result in a high incidence of respiratory disease in the cattle or other animals when they first arrive at the feedlot and soon thereafter. It has become common to administer antimicrobial drugs to calves and other feedlot animals at the time of arrival into a feedlot, in order to reduce the incidence and severity of respiratory illness in the feedlot cattle and other stock.
Without the use of antimicrobial agents, bovine respiratory disease (BRD), often referred to as the “bovine respiratory diseases complex” due to the multifactorial etiology has been one of the leading causes of economic loss to both the dairy and beef industries throughout the world. Excessive mortality, reduced weight gains, and the cost of treatment and prevention have placed a heavy burden on the industry.
The cost of death losses due to respiratory diseases vary around the world. Death losses in the U.S. are estimated to approach $1 billion annually. Losses in various European countries range from $75 to $120 million. Cattle with clinical or sub-clinical BRD do not gain weight or produce milk as well as healthy animals. Beef cattle with BRD gain less weight, have reduced feed efficiency and often produce a lower grade carcass at slaughter. Perino L. J. and Apley M., Bovine Respiratory Disease, in CURRENT VETERINARY THERAPY 4 (FOOD ANIMAL PRACTICE), 4TH ED., 446-455 (Howard J. L., Smith R. A., eds., 1999). A direct correlation between pulmonary lesions observed at slaughter and reduced weight gains has been established in cattle with sub-clinical infections. Whittem T. E. et al., J. Am. Vet. Med. Assoc., 209:814-818 (1996).
In addition to the production losses associated with mortality and morbidity, significant costs are associated with the treatment of BRD due to the costs of various therapeutic agents and the labor required to administer these agents, along with the extra labor to isolate and observe these animals.
The pathogenesis of BRD is thought to be due to the interaction of environmental and physiological stresses coupled with infectious agents, such as Mannheimia (Pasteurella) haemolytica, Pasteurella multocida and Haemophilus somnus that are considered part of the normal flora of the bovine upper respiratory tract. When environmental and physiological stress factors reduce the natural resistance, and inhibit the pulmonary defense mechanisms, these above organisms proliferate and colonize the lower respiratory tract. In addition, various bovine viruses such as infectious bovine rhinotracheitis virus (IBRV), bovine viral diarrhea virus (BVDV), bovine respiratory syncytial virus (BRSV), and parainfluenza 3 virus (PI-3) are known to have immunosuppressive effects in the lung.
Similarly, swine respiratory disease (SRD) also has a multifactional etiology. Bacterial infections caused by P. multocida, H. parasuis, Bordetella bronchiseptica, Actinobacillus pleuropneumoniae, Streptococcus suis, Salmonella cholerasuis and Mycoplasma sp. may result in respiratory disease in swine, resulting in significant economic losses. Stresses such as crowding, mixing and moving of pigs and transient viral infections may contribute to the intensification of the disease.
Any of the pathogens listed as possibly implicated in BRD or SRD may stimulate an excessive inflammatory process in the lungs by producing various toxins that stimulate the release of various cytokines, which up-regulate the inflammatory process, resulting in death or morbidity. M. haemolytica, considered the most virulent of these various organisms, also produces a leukotoxin that inhibits phagocytosis by leukocytes, thus further enhancing its ability to colonize the lower respiratory tract. This process often results in a bacterial bronchopneumonia.
Damage to host tissues caused by invading pathogens occur as neutrophils, pulmonary alveolar macrophages and natural killer cells destroy infected cells. As cell membranes are damaged, arachidonic acid is released. Arachidonic acid is the substrate for the formation of various prostaglandins and other eicosanoids. The release of these biological active substances is critical to driving the inflammatory response that results in pulmonary lesions. Mosier D. A., Vet. Clin. North Am. Food Animal Prac., 13:483-493 (1997).
In general, therapy for BRD should be directed at achieving the following goals:
1. Controlling the infection—In animals where the infectious process is halted early, the need for repeat treatment is significantly reduced (see Apley M. D. & Fejt V. R., Vet. Clin. North Am. Food Anim. Prac., 14:291-313 (1998)). The selection of the appropriate antimicrobial compound should be based on the antimicrobial sensitivity of the organism involved, the levels of the antimicrobial agent in the respiratory tract, the ease of administration, the potential for injection site tissue damage, and a dosing regime that minimizes the pain and stress associated with treatment.
2. Minimize the pulmonary damage—As the level of inflammation and subsequent pulmonary damage increases, the probability of repeat therapy increases and the rate of weight gain decreases. Lekeux P., Bovine Practitioner, 29:71-75 (1995); Scott P. R., J. Dairy Sci., 76(2):414-420 (1993).
3. Reduce pyrexia (fever)—Controlling the infection and reducing the inflammation will reduce the pyrexia, thus increasing the potential for recovery. The feeling of well-being that accompanies the reduction of pyrexia may also improve the intake of nutrients by suppressing inappetence associated with disease and pyrexia.
For years, antimicrobial therapy has been the mainstay of BRD therapy. There are many effective antimicrobial agents currently available for the treatment of BRD. NUFLOR®, an injectable formulation of the broad-spectrum antibiotic florfenicol, has emerged as one of the leading antibiotics on a global basis. NUFLOR® may be administered subcutaneously as well as intramuscularly. It is indicated for the treatment and control of BRD associated with M. haemolytica, P. multocida and H. somnus as well as for the prevention of respiratory disease in cattle at high risk of developing BRD associated with these bacteria. NUFLOR® is also indicated for the treatment of bovine interdigital phlegmon (footrot, acute interdigital necrobacillosis, infectious pododermatitis) associated with Fusobacterium necrophorum and Bacteroides melaninogenicus. 
There is a need for conveniently administered, stable compositions that may control and prevent the infections associated with bovine respiratory disease and other infectious diseases.